Substantially pure cilostazol and processes for making same

ABSTRACT

The present invention provides substantially pure cilostazol. The present invention also provides cilostazol particles that have reduced particle size.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.09/929,683 filed Aug. 14, 2001, now U.S. Pat. No. 6,515, 128 whichclaims the benefit of provisional application Ser. No. 60/225,362, filedAug. 14, 2000, which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to processes for preparing cilostazol.

BACKGROUND OF THE INVENTION

The present invention pertains to processes for preparing6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinoneof formula (I)

which is also known by the generic name cilostazol. Cilostazol inhibitscell platelet aggregation and is used to treat patients withintermittent claudication.

Cilostazol is described in U.S. Pat. No. 4,277,479 (“the '479 patent”),which teaches a preparation wherein the phenol group of6-hydroxy-3,4-dihydroquinolinone (“6-HQ”) of formula (II) is alkylatedwith a 1-cyclohexyl-5-(4-halobutyl)-tetrazole (“the tetrazole”) offormula (III). It is recommended to use an equimolar or excess amount upto two molar equivalents of the tetrazole (III).

The '479 patent mentions a wide variety of bases that may be used topromote the alkylation reaction, namely, sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate,potassium bicarbonate, silver carbonate, elemental sodium, elementalpotassium, sodium methylate, sodium ethylate, triethylamine, pyridine,N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine,1,5-diaza-bicyclo[4,3,0]-non-5-ene, 1,5-diaza-bicyclo[5,4,0]-undec-7-ene(“DBU”), and 1,4-diazabicyclo[2,2,2]octane.

The '479 patent states that the alkylation may be conducted neat or insolvent. Suitable solvents are said to be methanol, ethanol, propanol,butanol, ethylene glycol, dimethyl ether, tetrahydrofuran, dioxane,monoglyme, diglyme, acetone, methylethylketone, benzene, toluene,xylene, methyl acetate, ethyl acetate, N,N-dimethylformamide,dimethylsulfoxide and hexamethylphosphoryl triamide.

According to Examples 4 and 26 of the '479 patent, cilostazol wasprepared using DBU as base and ethanol as solvent.

In Nishi, T. et al. Chem. Pharm. Bull. 1983, 31, 1151-57, a preparationof cilostazol is described wherein 6-HQ is reacted with 1.2 molarequivalents of 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetraazole (“CHCBT,”tetrazole III wherein X═Cl) in isopropanol with potassium hydroxide asbase. Cilostazol was obtained in 74% yield.

One reason for using an excess of tetrazole as was done in Nishi et al.and recommended by the '479 patent is that CHCBT is unstable to somebases. When exposed to an alkali metal hydroxide in water for asufficient period, CHCBT undergoes elimination and cyclization to yieldbyproducts (IV) and (V).

Nishi et al.'s reported yield is based upon the limiting reagent 6-HQ.The yield with respect to CHCBT is 69%. In the economics of producing achemical on a large scale, improvements in chemical yield are rewardedwith savings in the chemical's production cost. CHCBT is an expensivecompound to prepare and should not be wasted. It would be highlydesirable to be able to realize further improvement in yield of thealkylation of 6-HQ with CHCBT and its halogen analogs in a way thatlowers the cost of producing cilostazol. In other words, it would bedesirable to further improve the yield of cilostazol by increasing thedegree of conversion of CHCBT to cilostazol, as opposed to, for example,improving the yield calculated from 6-HQ by increasing the excess oftetrazole or manipulating the reaction conditions in a way thatincreases the conversion of 6-HQ to cilostazol but at the expense ofpoorer conversion of CHCBT to cilostazol.

Although CHCBT is unstable to hydroxide ion, it is relatively stable inthe presence of non-nucleophilic organic bases. There are advantages tousing inorganic bases, however, that favor their selection over organicbases. Firstly, the phenolic proton of 6-HQ is labile. Thus, relativelynon-caustic and easily handled inorganic bases may be used to preparecilostazol. Further, inorganic bases are easier to separate from theproduct and are less toxic to the environment when disposed than organicbases are. Therefore, it would also be highly desirable to use aninorganic base while realizing an improvement in conversion of CHCBT tocilostazol.

SUMMARY OF THE INVENTION

The present invention provides improved processes for preparingcilostazol (I) by alkylating the phenol group of 6-HQ with the δ carbonof a 5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole.

In a first aspect, the invention provides a process wherein 6-HQ and awater soluble base are dissolved in water. A1-cyclohexyl-5-(4-halobutyl)-tetrazole is dissolved in awater-immiscible organic solvent. The two solutions are combined in thepresence of a quaternary ammonium salt phase transfer catalyst to form abiphasic mixture in which the 6-HQ and tetrazole react to producecilostazol. The purity of the cilostazol may be detected byreversed-phase high performance liquid chromatography (HPLC) usinggradient elution. The process may be practiced by a variety ofprocedures taught by the present invention. In one variation, a reactionpromoter, like sodium sulfate, is added to accelerate phase transfer of6-HQ into the organic solvent.

Another aspect of the present invention provides a preparation ofcilostazol from a single phase reaction mixture of 6-HQ and a1-cyclohexyl-5-(4-halobutyl)-tetrazole and a mixture of inorganic bases.The base mixture comprises an alkali metal hydroxide and alkali metalcarbonate. This process minimizes decomposition of the startingtetrazole and cilostazol by buffering the pH which results in improvedyield calculated based upon the tetrazole, the more precious of the twoorganic starting materials. A preferred embodiment wherein the alkalimetal hydroxide is added portionwise minimizes the formation of dimericbyproducts. In another preferred embodiment of the homogeneous process,the reaction mixture is dehydrated with molecular sieves before thetetrazole is added.

Yet another aspect of the present invention provides a pharmaceuticalcomposition comprising substantially pure cilostazol obtained by themethods of the present invention described above. By “substantiallypure” is meant having a purity equal to or greater than 98%.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising cilostazol particles of reduced particle size. By“reduced particle size” is meant about 90% of the particles having adiameter equal to or less than about 60 microns (d(0.9)≦60 microns). Thereduced particle size may be obtained by fine-milling or micronization.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparing cilostazol (I) byalkylating the phenol group of 6-HQ with the δ carbon of a5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole (“the tetrazole”). Thetransformation itself, depicted in Scheme 1 is known.

The present invention improves upon processes previously used to performthe chemical transformation depicted in Scheme 1 which result in agreater conversion of the tetrazole starting material to cilostazol. Theimprovements may be viewed as falling into one of two aspects of thepresent invention: (1) a heterogeneous, or biphasic, process employingphase transfer catalysis and improvements applicable to theheterogeneous process and (2) improvements applicable to a homogeneousprocess.

In a first aspect, the present invention provides a biphasic process forpreparing cilostazol by alkylating the phenol group of 6-HQ with a5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole using controlled phasetransfer methodology. For a discussion of the theory and generalapplication of phase transfer catalysis, See, Dehmlow, E. V.; Dehmlow,S. S., Phase Transfer Catalysis 3rd ed. (VCH Publishers: New York 1993).

According to the present inventive process, a solution of 6-HQ, awater-soluble base and a trialkyl ammonium phase transfer catalyst inwater is contacted with a solution of a5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole in a water-immiscible organicsolvent for a period of time sufficient to cause the tetrazole to besubstantially completely converted to cilostazol and then separating thecilostazol from the biphasic mixture.

The biphasic reaction mixture separates the base from the base sensitivetetrazole. Although not intending to be bound by any particular theory,it is believed that the 6-HQ phenolate anion complexes with thetetra-alkyl ammonium ion which increases its solubility in thewater-immiscible organic solvent. The complexed phenolate then entersthe water-immiscible phase and reacts with the tetrazole there.

Suitable phase transfer catalysts are ammonium salts such astricaprylylmethylammonium chloride (Aliquat® 336), tetra-n-butylammoniumbromide (“TBAB”), benzyltriethylammonium chloride (“TEBA”),cetyltrimethylammonium bromide, cetylpyridinium bromide,N-benzylquininium chloride, tetra-n-butylammonium chloride,tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide,tetra-ethylammonium chloride, benzyltributylammonium bromide,benzyltriethylammonium bromide, hexadecyltriethylammonium chloride,tetramethylammonium chloride, hexadecyltrimethyl ammonium chloride, andoctyltrimethylammonium chloride. More preferred phase transfer catalystsare Aliquat® 336, TBAB, TEBA and mixtures thereof, the most preferredbeing Aliquat® 336. The phase transfer catalyst may be used in astoichiometric or substoichiometric amount, preferably from about 0.05to about 0.25 equivalents with respect to the tetrazole.

Suitable bases are soluble in water but poorly soluble or insoluble inwater-immiscible organic solvents. Such bases are typically metal saltsof inorganic counterions. Preferred inorganic bases are hydroxide andcarbonate salts of alkali metals. More preferred inorganic bases areNaOH, KOH, K₂CO₃, Na₂CO₃ and NaHCO₃. The most preferred inorganic basein the heterogeneous process is NaOH.

The halogen atom of 5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole (X informula III) may be chlorine, bromine or iodine, preferably chlorine.Although the tetrazole may be used in any amount desired, it is mostdesirable to use a stoichiometric amount of tetrazole or less relativeto 6-HQ, more preferably about 0.9 molar equivalents.

Preferred water-immiscible solvents are toluene, hexanes,dichloromethane and mixtures thereof. An excess of water towater-immiscible solvent is preferred, although the ratio may varywidely. Preferred ratios of water to water-immiscible solvent range fromabout 0.5:1 to about 8:1 (v/v), more preferably from about 1:1 to about6:1.

According to one preferred procedure for preparing cilostazol, the 6-HQ,water-soluble base and phase transfer catalyst are dissolved in water.The tetrazole is dissolved in the water-immiscible solvent and the twosolutions are contacted and agitated, with optional heating, until thetetrazole is substantially consumed. Cilostazol may be isolated bycooling the reaction mixture to precipitate the cilostazol and thenfiltering or decanting the solutions. Cilostazol may be purified bymethods shown in Table 1 or any conventional method known in the art,including, for example, RP-HPLC using gradient elution, as discussedabove.

Alternatively, a biphasic mixture of the water-miscible organic solventand the aqueous solution of 6-HQ, water-soluble base and the phasetransfer catalyst is mixed and optionally heated while the tetrazole isslowly added to the stirred mixture. The slow addition of the tetrazolemay be either continuous or portionwise.

In yet another alternative procedure, an aqueous suspension of 6-HQ andthe phase transfer catalyst are contacted with the solution of tetrazolein the water-immiscible organic solvent. The biphasic mixture isagitated and optionally heated, while the water-soluble base is slowlyadded to the mixture. The slow addition may be either continuous as in aconcentrated aqueous solution of the base or portionwise.

Each of these preferred procedures may be modified to take advantage ofa further improvement, which is to add a reaction promoter to theaqueous phase. Reaction promoters are salts like sodium sulfate andpotassium sulfate that increase the ionic strength of aqueous solutionsbut do not form strongly acidic or basic aqueous solutions. The reactionpromoters decrease the solubility of 6-HQ in the aqueous phase andimprove the efficiency of phase transfer to the organic phase. Thepreferred reaction promoter is sodium sulfate. Preferably, the reactionpromoter is added in the amount of about 12-16% (w/v) with respect tothe aqueous phase.

In a second aspect, the present invention provides a process forpreparing cilostazol by alkylating the phenol group of 6-HQ with a5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole in a single liquid phasereaction mixture. 6-HQ and the tetrazole may be used in any amount,though it is preferred that the tetrazole be thelimiting reagent,preferably used in from about 0.9 to about 0.99 equivalents with respectto the 6-HQ. Suitable solvents for forming the single liquid phasereaction mixture of this aspect of the invention are non-aqueoushydroxylic solvents, which include 1-butanol, isopropanol, 2-butanol andamyl alcohol.

In this process, two inorganic bases are used to catalyze the reaction.One of the bases is an alkali metal hydroxide such as sodium orpotassium hydroxide. The other base is an alkali metal carbonate such assodium or potassium carbonate. The most preferred alkali metal ispotassium. Thus, preferred base mixtures are mixtures of potassiumhydroxide and potassium carbonate. The alkali metal hydroxide ispreferably used in an amount of from about 0.9 to about 1.2 equivalentswith respect to the 6-HQ and the alkali metal carbonate is preferablyused in an amount of about 0.1 to about 0.2 equivalents with respect tothe 6-HQ.

The 6-HQ, tetrazole, alkali metal hydroxide and alkali metal carbonatemay be added to the non-aqueous solvent in any order desired and at anyrate desired.

In one preferred procedure, 6-HQ, the tetrazole and the alkali metalcarbonate are added to the hydroxylic solvent along with a portion, e.g.about a one-fourth portion, of the alkali metal hydroxide. Thereafter,the remainder of the alkali metal hydroxide is added portionwise to thereaction mixture. It has been found that portionwise addition of thealkali metal hydroxide suppresses a byproduct that forms by thesubstitution of the halogen of the tetrazole by the 6-HQ lactamnitrogen.

Molecular sieves may be used to remove water from the single liquidphase reaction mixture before the tetrazole is added. Three and fourangstrom molecular sieves are preferred, with three angstrom sievesbeing most preferred. The molecular sieves may be stirred with thesolution to remove water formed by deprotonation of 6-HQ by KOH oradventitious water. Preferably, the molecular sieves are placed in asoxlet extraction funnel, the reservoir of a dropping funnel, or othersuitable apparatus mounted on the reaction vessel that will allowcirculation of vapor through the molecular sieves and return of thecondensate to the reaction vessel. The solution is then refluxed tocirculate water vapor over the molecular sieves. After the solution of6-HQ phenolate has been dehydrated, the tetrazole is added to thesolution to react with the 6-HQ phenolate to produce cilostazol.

In the process of Nishi et al., it was necessary to separate unreactedstarting materials and the organic base by column chromatography. It isdesirable in a large scale process to avoid chromatography andconcomitant production of spent solid phase. We have further discoveredthat cilostazol prepared according to the teachings of the presentinvention or by other methods can be selectively crystallized fromcertain solvents in high purity without the need for “clean up”chromatography to remove, for example, unreacted starting materials.Suitable recrystallization solvents are 1-butanol, acetone, toluene,methyl ethyl ketone, dichloromethane, ethyl acetate, methyl t-butylether, dimethyl acetamide-water mixtures, THF, methanol, isopropanol,benzyl alcohol, 2-pyrrolidone, acetonitrile, Cellosolve, monoglyme,isobutyl acetate, sec-butanol, tert-butanol, DMF, chloroform, diethylether and mixtures thereof.

The purity of the cilostazol may be detected by any means known in theart, including, for example, high performance liquid chromatography(HPLC), such as reversed-phase HPLC (RP-HPLC) using gradient elution. Asis known in the art, gradient elution involves steady changes in themobile phase composition during the chromatographic run. For determiningthe purity of cilostazol crystalized according to the present invention,a RP-8 column should be used. The eluent components of the mobile phaseare water and acetonitrile and the mobile phase is preferably controlledby a gradient program starting with an initial element of 100% wateruntil a 1:1 ratio of the two components is obtained. The chromatographicsystem is equipped with an ultraviolet detector set at 254 nanometers.This RP-HPLC method allows the detection of cilostazol-relatedimpurities until a level of at least 0.02% relative to the sampleconcentration.

In a further aspect of the present invention, when a pharmaceuticalcomposition comprising cilostazol prepared according to the presentinvention is formulated for oral administration, the compound ispreferably processed to have a reduced small particle size. Methods ofobtaining reduced particle size of a compound are well known in the artand include, for example, processes such as fine-milling andmicronization. Accordingly, in one embodiment of the present invention,the cilostazol prepared according to the present invention isfine-milled under suitable conditions of mill rotation rate and feedrate to where 90% of the particles have a diameter of about 60 microns.In another embodiment, the cilostazol is micronized by being passedthrough an air jet mill at a suitable feed air pressure, grinding airpressure, feed rate, and rotation rate to where 90%. of the particleshave a diameter equal to or less than about 15 microns. The cilostazolmay then be formulated into a pharmaceutical composition or dosage formfurther comprising one or more pharmaceutically acceptable excipients.Such compositions and dosage forms include, for example, compactedtablets, powder suspensions, capsules, and the like.

The invention will now be further illustrated with the followingexamples, which offer highly specific procedures that may be followed inpracticing the invention but which should not be construed as limitingthe invention in any way.

EXAMPLES Example 1

Preparation of Cilostazol Using a Phase Transfer Catalyst

A 1 L reactor was charged with 6-HQ (16.5 g, 0.1011 moles), and NaOH (1eq.) in water (90ml). To this solution was add toluene (15 ml) and CHCBT(22.22 g, 0.0915 moles), Na₂SO₄ (17 g) and catalyst (1.9 g) (aliquat336). The mixture was heated to reflux for 8 h. After this period oftime, the mixture was cooled to room temperature, the solid was filteredand washed with water and methanol to afford the crude product (29 g,yield 88%; purity by reversed-phase HPLC using gradient elution˜99%).

Example 2

Preparation of Cilostazol with Addition of CHCBT in One Portion

6-HQ (10 g, 0.0613 moles), KOH (4.05 g, 0.0722 moles), K₂CO₃ (1.5 g,0.011 mole), CHCBT (18 g, 0.0742 moles) and n-BuOH (130 ml) were heatedat reflux for ˜5 hours. After cooling of the reaction mixture to roomtemperature the solid was filtered, washed with n-BuOH and water. Thecrude product (19.7 g, 85% yield, 98.7% pure) was recrystallized fromn-BuOH (10 vol.) to give cilostazol crystals (yield 94%, 99.6% pure).

Example 3

Preparation of Cilostazol by Addition of the Base in Portions

6-HQ (10 g, 0.0613 moles), KOH (1.01 g, 0.018 mole), K₂CO₃ (1.5 g, 0.011mole), CHCBT (13.4 g, 0.0552 moles) and 130 ml n-BuOH were heated atreflux for 1 hour. After 1 hour, a second 1.1 g portion of KOH was addedand the reflux was continued. The procedure was repeated with twoadditional 1.1 g portions of KOH. After the addition of the whole KOHthe reaction was continued for an additional hour. The reaction mixturewas cooled to room temperature, the solid was filtered and washed withn-BuOH and dried to afford the product (15.6 g, 56% yield, 98.3% pure).

Example 4

Preparation of Cilostazol Using Molecular Sieves as Dehydrating Agent

A three neck flask equipped with condenser and a soxlet extractionfunnel containing molecular sieves 3 Å (28 g) was charged with 6-HQ (10g, 0.0613 moles), KOH (4.05 g, 0.0722 moles) and K₂CO₃ (1.5 g, 0.011moles) and 130 ml n-BuOH. The mixture was heated to reflux and thereflux was maintained passing the solvent over the molecular sieves.After 30 minutes, CHCBT (18 g, 0.0742 moles, 1.2 equivalents) was addedand the reflux was continued for about 5 h. Then, the reaction mixturewas cooled and the product was filtered and washed with n-BuOH. Theyield after drying was 14.4 g (62%, 98.3% pure).

Example 5

Preparation of Cilostazol Using an Excess of 6-HQ

6-HQ (10 g, 0.0613 moles), KOH (4.05 g, 0.0722 moles), K₂CO₃ (1.5 g,0.011 mole), CHCBT (13.4 g, 0.0552 moles) and 130 ml n-BuOH were heatedat reflux for 5 hours. After cooling of the reaction mixture to roomtemperature the solid was filtered and washed with n-BuOH and water; thematerial was dried to give the product cilostazol (15.93 g, 76.2% yield,98.5% pure).

Example 6

Crystallization of Cilostazol from Recrystallization Solvents

Table 1 provides conditions for selectively crystallizing cilostazolfrom mixtures containing minor amounts of 6-HQ and CHCBT and obtainingsubstantially pure cilostazol.

TABLE 1 Example Solvent Volume* Recommended Procedure Purity 6 n-BuOH 1097.2 7 n-BuOH 20 98.1 8 Acetone 20 Slurry. Reflux. Cool to r.t. 98.65 9Toluene 20 Dissolve at reflux. Cool to r.t. 98.60 10 Methyl ethyl ketone11 Dissolve at reflux. Cool to r.t. 99.33 11 CH₂Cl₂ 4 Dissolve atreflux. Cool to r.t. 98.82 12 Ethyl acetate 10 Slurry at reflux 1 h.Cool to r.t. 97.50 13 MTBE 10 Slurry at reflux 1 h. Cool to r,t, 94.0614 2:1 DMA-H2O 10 Dissolve in DMA at ˜70-80° C. Add water. Cool to r.t.Precipitate at 65° C. 15 THF 13 Dissolve at reflux. Cool to r.t. 16Methanol 3 Dissolve at reflux. Cool to r.t.. 99.16 Precipitate at 55° C.17 Acetone 2.5 Slurry at reflux for 1 h. Cool to 99.12 r.t. 18 Ethanol12.5 Dissolve at reflux. Cool to r.t. 98.90 19 Isopropanol 19 Dissolveat reflux. Cool to r.t. 98.75 20 Acetone 33 Dissolve at reflux. Cool to40° C. 98.90 21 Benzyl alcohol 2 Dissolve at 55° C. Cool to r.t. 98.8522 2-Pyrrolidone 3.5 Dissolve at 65° C. Cool to r.t. 23 Acetonitrile 6.5Dissolve at reflux. Cool to 30° C. 98.70 24 2-BuOH 5 Dissolve at ˜90° C.Cool to r.t. 94.80 25 Cellosolve 3 Dissolve at ˜100° C. Cool to r.t.98.80 26 Monoglyme 13 Dissolve at reflux. Cool to r.t. 97.06 27iso-butyl-acetate 23 Dissolve at reflux (115° C.). Cool 97.50 to r.t. 28n-BuOH 20 Dissolve at reflux. Treat with 99.14 decolorizing agents, (SX1activated carbon and tonsil silicate). Cool to r.t. 29 MeOH 10 Dissolveat reflux. Cool to r.t. 99.92 30 MeOH 10 Dissolve at reflux. Cool tor.t. 99.93 31 MeOH 10 Dissolve at reflux. Cool to r.t. 99.95 *Relativeto the volume of cilostazol

Example 32

Reduction of Particle Size and Particle Size Distribution of Cilostazol

Cilostazol obtained from Examples 1-6, is fine-milled by being passedthrough a pin mill at a mill rotation rate of 10500 rpm and a feed rateof 15 kg/hr to where 90% of the cilostazol particles have a diameter ofabout 60 microns.

Example 33

Cilostazol is micronized by being passed through an air jet mill at afeed rate of 20 kg/hr, a feed air pressure of 7 bars, a grinding airpressure of 4 bars to where 90% of the cilostazol particles have adiameter of less than about 15 microns. The rotation rate of the jetmill is 300 mm.

It should be understood that some modification, alteration andsubstitution is anticipated and expected from those skilled in the artwithout departing from the teachings of the invention. Accordingly, itis appropriate that the following claims be construed broadly and in amanner consistent with the scope and spirit of the invention.

We claim:
 1. Cilostazol in a purity equal to or in excess of 99.6%. 2.The cilostazol of claim 1 wherein the cilostazol is purified by reversephase high performance liquid chromatography.
 3. A pharmaceuticalcomposition comprising the cilostazol of claim 1 and a pharmaceuticallyacceptable excipient.
 4. Cilostazol in powder form and having a particlesize distribution in which d(0.9) is equal to or less than about sixtymicrons.
 5. The cilostazol of claim 4 wherein the d(0.9) is equal to orless than about 15 microns.
 6. A pharmaceutical composition or dosageform comprising the cilostazol of claim 4 and a pharmaceuticallyacceptable excipient.
 7. The pharmaceutical composition or dosage formof claim 6 that is a powder suspension in a liquid.
 8. Thepharmaceutical composition or dosage form of claim 6 that is a compactedtablet.